1. Field of the Invention
Objects of the present invention are stable, aqueous liquid formulations of G-CSF, substantially consisting of G-CSF and a sugar alcohol, a surfactant, a buffer substance at a pH value of about 4.1 to 4.4, and optionally also amino acids and/or glycerol and/or carbohydrates and/or preservatives.
2. Description of Related Art
Many of the hitherto known dosage forms for protein agents have disadvantages. For instance, certain preparations contain pharmaceutical additives or excipients that cannot readily be categorized as harmless from a medical point of view. Due to their origin and physico-chemical properties, polymers and proteins bear a certain risk potential with respect to their suitability as pharmaceutical additives. Proteins of human or animal origin as well as proteins obtained from cell cultures bear a potential residual risk of viral contaminations. Due to their antigenic properties, other protein-like contaminations, which are difficult to detect analytically, can also trigger immunological reactions in humans. Moreover, proteins of animal origin can trigger immunological reactions in humans due to their species-specific properties in general. Long-term reactions upon reapplication of such proteins at a later point in time are also possible.
The admixture of compounds having a high molecular weight can also be problematic. Polymers can be accumulated in the body due to their high molecular mass and can therefore remain in the body for a long time, in case there is no biodegradation. This is, in particular, to be feared in case of subcutaneous application, as removal and distribution via the bloodstream is much more delayed in comparison to intravenous application. Depending on the molar mass, polymers can also have antigenic properties. Furthermore, the purity of polymers is difficult to ensure due to the catalysts used for production or due to the presence of monomers other polymer fragments. The use of polymers in liquid pharmaceutical dosage forms is thus to be avoided as far as possible, in particular with subcutaneously applicable dosage forms.
Furthermore, it is known from the literature that particularly non-glycosylated forms of G-CSF, when compared to glycosylated G-CSF obtained from CHO cells, are extremely unstable owing to oxidation and/or aggregation. It is therefore extremely difficult to stabilize non-glycosylated forms of G-CSF and specifically selected measures are required to formulate said molecule into a stable dosage form.
The use of surfactants for stabilizing G-CSF is principally to be avoided from a medical point of view as said surfactants may trigger local irritations. Formulations having a very low pH value, in particular in case of a subcutaneous application, can also lead to local incompatibilities in patients, e.g. pain and local tissue irritation, as said pH value lies below the physiological range from pH 7.0 to 7.5 that is present in the tissue.
The recently published international application WO 2005/042024, similarly to the teachings of EP 373 679, teaches a way of obtaining stable pharmaceutical compositions of G-CSF by keeping said compositions, inter alia, free of surfactants and, in accordance with the compositions described in the Examples, by providing the buffer at a very low concentration. There are no indications given with respect to the acceptability of the medicaments described therein.
In the European patent application EP 1 129 720, preparations of G-CSF having a pH value in the range from 5 to 8 are described, wherein sulfate is supposed to stabilize the G-CSF contained in the preparation. Again, there are no indications given with respect to the acceptability of the G-CSF preparations described therein.